Improving beta cell function by mesenchymal stromal cells: novel mechanisms and cell-free translational potential

通过间充质基质细胞改善β细胞功能：新机制和无细胞翻译潜力

• 批准号: MR/W002876/1
• 负责人: Peter Jones
• 金额: $ 51.72万
• 依托单位: King's College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2022
• 资助国家: 英国
• 起止时间: 2022 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FW002876%2F1
• 关键词: Improving; beta; cell; function; mesenchymal

Islet transplantation offers the prospect of a cure for type 1 diabetes (T1D) rather than merely treating the symptoms with insulin. However, a major problem with islet transplantation as a treatment is the significant loss of graft function (up to 80%) which occurs in the 24-48 hours immediately after transplantation. This loss of function is partly because the isolated islets in the graft are fragile and easily damaged, and partly because the graft environment, inside the liver bloodstream, reacts to the graft by causing inflammation which irreversibly damages the islets. In experimental animals co-transplanting "helper" cells known as mesenchymal stromal cells (MSCs) with islets improves graft function and survival, and suppresses inflammation, but this is not technically feasible in clinical human islet transplants. We are therefore studying how MSCs improve islet graft survival and function to replicate the beneficial effects of MSCs in an "MSC-free" system. We have previously shown that some of the beneficial effects of MSCs can be attributed to biologically active molecules which they secrete and can be replicated merely by supplying the molecules to the islets before transplantation. In this project we plan to look at two other mechanisms through which MSCs may influence islet function. First, like many other cell types, MSC release small, membrane bound vesicles ("extracellular vesicles"; EVs) to communicate with other cells by transporting biologically active molecules and other cellular components. We will assess whether treating islets with MSC-derived EVs has beneficial effects on their functional survival and thus on the outcomes of islet transplantation. Second, we have recently reported that MSCs can transfer some of their mitochondria - subcellular organelles which are vital for normal cell function - to functionally-compromised islet cells. We will investigate how mitochondria are transferred between MSCs and islet cells, and whether this is associated with improved islet function. Information gained from this project will inform how best to design "cell-free" treatments of human islets prior to transplantation to improve the functional survival of the islet graft, particularly within the first few days after transplantation, and so improve the clinical outcomes for individual graft recipients.

胰岛移植为治愈 1 型糖尿病 (T1D) 提供了前景，而不仅仅是用胰岛素治疗症状。然而，胰岛移植治疗的一个主要问题是移植后 24-48 小时内发生的移植物功能显着丧失（高达 80%）。这种功能丧失的部分原因是移植物中孤立的胰岛脆弱且容易损坏，部分原因是肝血流内的移植物环境对移植物产生反应，引起炎症，从而不可逆地损害胰岛。在实验动物中，将称为间充质基质细胞（MSC）的“辅助”细胞与胰岛共同移植可改善移植物功能和存活，并抑制炎症，但这在临床人类胰岛移植中在技术上不可行。因此，我们正在研究间充质干细胞如何提高胰岛移植物的存活率和功能，以在“无间充质干细胞”系统中复制间充质干细胞的有益作用。我们之前已经表明，间充质干细胞的一些有益作用可归因于它们分泌的生物活性分子，并且仅通过在移植前向胰岛提供分子即可复制。在这个项目中，我们计划研究 MSC 影响胰岛功能的另外两种机制。首先，像许多其他细胞类型一样，MSC 释放小的膜结合囊泡（“细胞外囊泡”；EV），通过运输生物活性分子和其他细胞成分与其他细胞进行通讯。我们将评估用 MSC 衍生的 EV 治疗胰岛是否对其功能存活以及胰岛移植的结果产生有益影响。其次，我们最近报道间充质干细胞可以将一些线粒体（对正常细胞功能至关重要的亚细胞细胞器）转移到功能受损的胰岛细胞。我们将研究线粒体如何在间充质干细胞和胰岛细胞之间转移，以及这是否与改善胰岛功能有关。从该项目获得的信息将告知如何在移植前最好地设计人类胰岛的“无细胞”治疗，以提高胰岛移植物的功能存活率，特别是在移植后的最初几天内，从而改善个体的临床结果移植受者。